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Eur J Cardiothorac Surg 2002;22:995-999
© 2002 Elsevier Science NL

Peripheral small-sized (2 cm or less) non-small cell lung cancer with mediastinal lymph node metastasis; clinicopathologic features and patterns of nodal spread

Shun-ichi Watanabe*, Makoto Oda, Yoshio Tsunezuka, Tetsuhiko Go, Yasuhiko Ohta, Go Watanabe

Kanazawa University School of Medicine, Kanazawa 920-8641, Japan

Received 10 March 2002; received in revised form 2 September 2002; accepted 4 September 2002.

* Corresponding author. Present address. Division of Thoracic Surgery, National Cancer Center Hospital, Tsukiji 5-1-1, Tokyo 104-0045, Japan. Tel.: +81-3-3542-2511; fax: +81-3-3542-3815
e-mail: syuwatan{at}ncc.go.jp


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Objective: The diagnosis of small-sized (2 cm or less) non-small cell lung cancer (NSCLC) has increased with the development of computed tomography (CT), whereas unexpected extensive multiple-level mediastinal involvement has been occasionally detected in this small-sized lung cancer. To establish the optimal surgical strategy, we retrospectively analyzed the clinicopathologic features, efficacy of preoperative investigations and lobe specific patterns of nodal spread in small-sized NSCLC with mediastinal involvement. Methods: Among 1550 resected lung cancer cases between 1981 and 2000, 267 (17.2%) had peripheral small-sized NSCLC. Of these, 29 patients (10.8%) with mediastinal lymph node involvement who underwent pulmonary resection and systematic nodal dissection were reviewed. Results: Among 29 patients, 27 patients (93.1%) were adenocarcinoma, and 51.7% (15/29) showed no lymph node enlargement on CT (cN0). Surgical pathology revealed multiple-level mediastinal involvement in 65.5% (19/29) of all patients and 60.0% (9/15) of cN0 patients. All of right upper lobe tumors (n=11) showed multiple-level involvement. Thallium-201 single photon emission computed tomography (201Tl-SPECT) was positive for increased focal uptake in the mediastinum in 72.7% (8/11) of patients. Conclusions: The vast majority of cases were adenocarcinoma, and two thirds of them showed multiple-level mediastinal involvement, even in cN0 patients. We thus recommend to perform systematic nodal dissection or meticulous sampling for accurate intrathoracic staging, especially for right upper lobe tumor. 201Tl-SPECT appears to be more sensitive preoperative investigation for mediastinal metastasis compared with CT scan.

Key Words: Small-sized lung cancer • Mediastinal lymph node metastasis • Systematic nodal dissection • Computed tomography (CT) • Thallium-201 single photon emission computed tomography (201Tl-SPECT)


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
The diagnosis of small-sized (2 cm or less in diameter) lung cancer has gradually increased with the development of computed tomography (CT) scanner in recent decades. Although part of peripheral small-sized lung cancer group may become a good candidate for limited resection, mediastinal node involvement is detected with an incidence of 10–15% [1,2], occasionally in the multiple stations. To establish the optimal therapeutic strategy for small-sized lung cancer, we conducted the retrospective analysis of the clinicopathologic features and patterns of nodal spread in peripheral small-sized non-small cell lung cancer (NSCLC) with mediastinal lymph node metastasis.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Patients
From January 1981, the year we introduced the first CT scanner, to December 2000, 1550 patients underwent pulmonary resection for primary lung cancer at Kanazawa University Hospital. Among them, 29 patients (1.9%) with peripheral small-sized (2 cm or less in maximum diameter) NSCLC and mediastinal lymph node metastasis who underwent pulmonary resection and systematic nodal dissection were retrospectively reviewed. They corresponded to 10.8% of all peripheral small-sized NSCLC during the same period (n=267). The maximum diameter of the primary tumor was measured by pathologists on formalin-fixed surgical specimens.

2.2. Preoperative investigations
Our criterion for lymph node enlargement on chest CT film is more than 1.0 cm in short axis of nodal stations. We used Naruke map and the Classification of Lung Cancer issued by the Japan Lung Cancer Society for the designation of dissected nodal stations. Among clinical N2 patients, any patient with bulky N2 (more than 2 cm in diameter) or multi-station N2 on CT was excluded from the candidate for resection. Thallium-201single photon emission computed tomography (201Tl-SPECT) was preoperatively performed in 11 patients. Thallium-201 chloride was injected intravenously, and tomographic scans were obtained 15 min (early scan) and 3 h (delayed scan) after injection using a rotating gamma camera system. Then we differentiated malignant from benign lesions and evaluated mediastinal involvement by calculating the delayed ratio and the retention index [3]. Transbronchial lung biopsy (TBLB) was performed through fiberoptic bronchoscopy in 13 out of 29 patients to obtain the biopsy specimen and determine the lesions to be malignant. The remaining 16 patients plus eight TBLB negative lesions, totally 24 lesions were determined to be malignant intraoperatively by frozen section examination. No percutaneous biopsy or mediastinoscopy was employed in our series. We measured the plasma carcino-embryonic antigen (CEA) level mainly as an indicator of nodal involvement in adenocarcinoma patients. CEA was measured in 22 patients by enzyme immunoassay and 5 ng/ml was used as the cut-off value. No induction therapy was administered in this series.

Mean values are expressed as mean±standard deviation throughout the article.

2.3. Operative procedure
All tumors were removed through posterolateral thoracotomy. After pulmonary resection, systematic nodal dissection was conducted from upper to lower mediastinum. Even in left lung cancer patients, the upper mediastinal lymph nodes were routinely dissected by dividing the ligamentum arteriosm and mobilizing the aortic arch.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
3.1. Patient characteristics
The patient characteristics are shown in Table 1. The patients consisted of 19 men and ten women with a mean age of 59.0±9.8 years (range 39–72). Twenty-two cases (76.9%) were asymptomatic and detected by chest X-ray films, 16 cases from mass-screening examinations and six by chance. Most tumors were primarily located in the right lobe (n=21 [72.4%]; upper, n=11; middle, n=1; lower, n=9). Lobectomy was performed for 27 (93.1%) patients. All tumors were more than 10 mm in size, 11–15 mm in nine cases and 16–20 mm in 20 cases. The tumor cell types were adenocarcinoma in 27 (92.3%), squamous cell carcinoma in 0, adeno-squamous cell carcinoma in 1 (3.8%) and large cell carcinoma in 1 (3.8%). Tumor differentiation of these 27 adenocarcinoma cases was well differentiated in 9, moderately differentiated in 13 and poorly differentiated in 5. Preoperative evaluation of nodal status by CT was N0 in 15 (51.7%) cases, N1 in 1 (3.5%) and N2 in 13 (44.8%); thus 55.2% of the patients were understaged preoperatively.


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  		Table 1. Patient characteristics in small-sized non-small cell lung cancer patients with mediastinal lymph node involvement

 
3.2. Preoperative investigations
Preoperative plasma CEA level was measured in 22 patients. Their mean value was 35.5±82.2 ng/ml, and 11 patients (50.0%) showed an abnormal level (Table 2). Four cases showed more than 50 ng/ml, and the maximum value was 371.6 ng/ml.


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  		Table 2. Preoperative investigations for primary and mediastinal sitesa

 
201Tl-SPECT was employed in 11 patients. Of these, ten patients (90.9%) were diagnosed as lung cancer by calculating the retention index (RI) of the primary site. Among these ten patients, eight patients showed high RI at both the primary and mediastinal sites and two only at the primary site. The sensitivity for mediastinal node involvement was 72.7% (8/11) (Table 2).

Among 13 patients performed fiberoptic bronchoscopy, five patients (38.5%) were preoperatively diagnosed to be malignant by TBLB (Table 2).

3.3. Levels of the mediastinal lymph node metastasis
3.3.1. Number of metastatic station levels grouped by a lobe of origin
Table 3 shows the number of metastatic station levels grouped by a lobe of origin. In total, 65.5% (19/29) of all patients and 60.0% (9/16) of cN0 patients showed multiple-level metastasis. Notably, all of the right upper lobe origin cases (n=11) developed multiple-level metastasis. The incidence of multiple-level metastasis in the right lower and left upper lower tumor were 33.3% (3/9) and 50% (4/8), respectively. Three patients from right upper lobe and two from right lower lobe showed extensive involvement of four or more levels.


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  		Table 3. Levels of metastatic stations grouped by a lobe of origin.

 
3.3.2. Distribution of metastatic stations
Fig. 1 demonstrates the distribution of mediastinal lymph node metastasis grouped by a lobe of origin, Figs. 1A,B shows the right and the left side tumor, respectively. Right upper lobe tumors developed extensive multi-level involvement within the upper, middle and lower mediastinum. Three out of nine (33.3%) right lower lobe primary cases presented upper mediastinal nodal involvement, and all of them showed involvement of subcarinal node (station #7) as well.



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  		Fig. 1. Distribution of mediastinal lymph node metastases grouped by a lobe of origin (A, right side tumor; B, left side tumor). Multiple-level mediastinal metastases from the right upper (•), right middle ({blacktriangleup}), right lower ({blacksquare}) and left upper ({diamondsuit}) lobe, and single-level metastasis from the right upper ({circ}), right middle ({triangleup}), right lower ({square}) and left upper ({diamond}) lobe are drawn.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
The detection of small-sized lung cancer is increasing with the development of helical CT scanner, however, the preoperative evaluation of intrathoracic nodal status with CT scan is remaining to be difficult mainly because many cancer positive nodes of normal size can be seen on pathological examination especially in adenocarcinoma cases. As shown in Table 1, more than half (55.2%) of the patients were preoperatively understaged on CT. In our institution, 73 (13.9%) out of 526 patients preoperatively diagnosed stage I by CT from 1981 to 1997 were revealed to be N2–3 on pathological examination after surgery [4]. Preoperative evaluation of nodal status by CT scan is thus not accurate enough to decide the appropriateness of limited resection for small-sized lung cancer [5,6].

Furthermore, even though the nodes are revealed to be N0 on pathological examination, adenocarcinoma is reported to show vessel invasion with high incidence [7]. We previously reported that 20.5% of small-sized adenocarcinoma have shown hilar or mediastinal nodal involvement in our institution, and advocated that nodal stations should be dissected or at least be sampled meticulously in most small-sized adenocarcinoma cases for accurate intrathoracic staging [1]. In this series, as shown in the results, nearly two thirds (65.5%) of all patients and 60% of cN0 patients showed multiple-level mediastinal metastases. Keller and associates (Eastern Cooperative Oncology Group) [8] reported that complete mediastinal lymph node dissection had identified significantly more levels of mediastinal involvement. Apart from the discussion as to the impact of nodal dissection on long-term survival in lung cancer patients [8–10], above-mentioned facts imply that systematic nodal dissection (SND) is indispensable even in small-sized adenocarcinoma patients to evaluate the disease extent. We must be careful to perform a limited resection or video-assisted thorascopic surgery for small-sized adenocarcinoma patients.

Although an aggressive nodal dissection has been performed even for the left side tumor in our institution [10], 72.4% of tumors were located on the right side. Riquet [11] noted that the right lung has a lot of direct passages going into the mediastinum. Notably, as shown in the present study, all right upper origin tumors developed extensive multiple-level mediastinal involvement within the upper, middle and lower mediastinum. Complete nodal dissection or meticulous sampling of all stations in the mediastinal stations would be indispensable, especially for the right upper lobe tumor even though the lesion is small in size. As for tumors located in the lower lobe, one third (3/9) of tumors showed metastases to the upper mediastinum in our series. This fact might suggest the necessity of upper mediastinal lymph node dissection for lower lobe tumors, however, all lower lobe tumors with upper mediastinal involvement showed concomitant subcarinal node (#7) involvement. Therefore the lower lobe tumor without subcarinal involvement would not require upper mediastinal dissection, as Okada [12] and Naruke [13] previously reported. There will exist a group of adenocarcinoma showing ground-glass attenuation on high resolution CT (HRCT) for which SND is considered to be unnecessary [1,6,14]. To avoid unnecessary dissection in small-sized cancer, we need to tailor the process of nodal dissection to each case considering the lobe specific disease extent as we described above and HRCT findings.

Regarding the preoperative investigation, we herein showed the usefulness of conventional investigations, CEA measurement and 201Tl-SPECT. CEA is an antibody extracted from colon cancer, and initially used as a specific tumor marker for digestive cancers [15]. It has also been revealed to be useful for the lung cancer, especially in adenocarcinoma patients [16,17]. In this study, 50.0% (11/22) of advanced small-sized lung cancer patients showed abnormal plasma CEA levels. This incidence is similar to that of overall stage IIIA patients with mediastinal involvement reported by Vincent [16]. Moreover, four out of these 11 patients (36.4%) with abnormal CEA were diagnosed N0–1 on CT preoperatively. Therefore in the case of small-sized lung cancer patients showing abnormal plasma CEA levels, it would be helpful to perform mediastinoscopy or careful nodal dissection even though mediastinal nodes were negative on CT investigation.

The rationale of accumulation of 201Tl in the primary lesion or metastatic nodes is considered to be due to the activity of Na, K-ATPase within the tumor cells because the nature of 201Tl is similar to that of potassium. Tonami [3] reported that a retention index calculated with an early and a delayed scan had been a useful indicator not only for discriminating between benign and malignant tumors, but also for detecting mediastinal metastasis with 71.4% of sensitivity. In this study, 90.9% (10/11) patients showed accumulation in the primary site and 72.7% (8/11) patients showed mediastinal accumulation on 201Tl-SPECT. Half of the patients (4/8) with mediastinal accumulation on 201Tl-SPECT showed negative mediastinal node on CT. Although the number of cases is small in our series, we consider 201Tl-SPECT to be a useful investigation which provides helpful information. Ishibashi and associates [18] recently reported a significant correlation between the 201Tl delayed index and the cancer cell proliferation in lung cancer. Small-sized lung cancer with mediastinal involvement may be one of the groups showing high proliferation ratio of active cancer cells. As recently reported, fluorodeoxyglucose – positron emission tomography (FDG-PET) is deemed to be a more sensitive investigation with good spatial resolution for the primary and mediastinal sites in lung cancer, because the radiopharmaceutical is concentrated by metabolically active cancer cells [19]. Although accumulation of a number of small-sized lung cancer cases investigated by PET scan is required, FDG-PET will play an important role in the establishment of optimal therapeutic strategy for small-sized lung cancer.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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